Myocardial triglyceride content at 3 T cardiovascular magnetic resonance and left ventricular systolic function: a cross-sectional study in patients hospitalized with acute heart failure

¹
H-MRS performed on 1.5 T MR scanner has been shown to be a reliable and reproducible
imaging modality for the assessment of human myocardial TG content 11]–13], while the high-field 3 T MR scanner, as used in this study, has significantly greater
signal-to-noise ratio coupled with increased spectral resolution and has shown to
be more accurate for in vivo quantification of myocardial fat fraction as compared
to 1.5-Tesla 20].
¹
H-MRS research study on formalin-fixed specimens of human hearts at various locations
demonstrated that septal fat content is largely representative of myocardial TG deposition
21]. Herein, we applied
¹
H-MRS in the interventricular septum to assess the heart of a subgroup of HF patients
6?~?12 months after hospitalization on 3-T MR scanner. To the best of our knowledge,
this is the first in vivo study specifically investigating the relation of different
myocardial TG components and functional cardiac parameters on post-hospitalized HF
patients with 3-T CMR plus
¹
H-MRS. Our main results indicated an association between the accumulation of myocardial
TG components and the damaged heart. First, myocardial UFA content was significantly
higher in our patients than in controls, even those showed good recovery from HF with
their LVEF restoring to the normal range. Second, the myocardial UFA/TG ratio was
positively correlated with LV mass and LVEDV. The reproducibility of our results was
confirmed by Bland-Altman plots 19]. Taken together, the current study support the clinical utility of 3 T
¹
H-MRS for measuring myocardial TG components in patients who were hospitalized with
acute HF.

In this study, our patients had significantly increased myocardial UFA content as
compared with controls. Intriguingly, there was a stepwise decrease of myocardial
UFA concentrations when comparing patients with low LVEF, normal LVEF, and controls
(p?=?0.02). The standard deviation of UFA/W was significantly larger in patients with
low EF compared with values observed in patients with normal EF and controls (Table 3). This observation can be explained by the wider range of EF observed in patients
with low EF, ultimately resulting in a higher standard deviation (12.3) than those
observed in both subjects with normal EF (8.3) and controls (7.6, Table 2). The differences in the standard deviations are unlikely to be caused by a suboptimal
UFA quantification. Accordingly, our phantom study clearly demonstrated the reproducibility
of measuring and fitting UFA (Additional file: 1 Figure S1). The relationship of accumulation of myocardial TG in patients with cardiomyopathy
has been previously reported, but with different results 14], 15], 22], 23]. Graner et al. 22] reported that myocardial TG content decreased in non-diabetic subjects with dilated
cardiomyopathy, however, showed the opposite results in those with diabetic heart
disease 14], 23]. Nakae et al. 15] found that myocardial TG may be related to the specific cause of disease rather than
the severity of cardiac dysfunction. Nevertheless, notable finding from the current
study is that myocardial UFA, instead of FA and TG, was increased in post-hospitalized
HF patients and was related to the severity of LV systolic function.

LV mass and LVEDV of our patients were positively correlated with myocardial UFA/TG
ratio but were negatively correlated with myocardial FA/TG ratio. Their correlations
with TG/W were not significant. In a series of 15 healthy humans evaluated with 1.5 T
1H- MRS, Szczepaniak et al. 24] found that increased myocardial triglyceride content was accompanied by elevated
LV mass. In another series with ten male endurance athletes and 15 healthy male controls
evaluated with 1.5 T
¹
H- MRS, Sai et al. 25] showed that the myocardial TG content was significantly lower in the athlete group
than in the control group, and was negatively correlated with LV mass and volume.
We believe that the study participants selection and MRI scanner field strength may,
at least, partly account to the discrepancies of our results from those previously
reported. Of note, the averaged TG/W ratio found in our control group was 15.3 which
fell between those of our stable HF (11.8) and unstable HF group (17.2). Accordingly,
our control subjects had a mean body mass index of 26.3 kg/m
²
, being overweight according to the WHO definition. In addition, the TG/W ratio is
characterized by a diurnal course, with higher levels in the morning than in the evening
9]. The impact of these potential confounders on the TG/W needs further scrutiny.

It has been reported that myocardial TG accumulation promotes the development of cardiac
hypertrophy, ventricular dysfunction, and interstitial fibrosis 5]. Although an increased TG deposition in the pancreatic islets has been linked to
non-insulin-dependent diabetes mellitus 26], the potential relationship between myocardial TG accumulation and diabetic heart
disease remains unclear. An animal study has demonstrated that increased TG content
within the myocardium contributes to the development of cardiac dysfunction through
lipotoxic effects 27]. In patients with HF, accumulation of myocardial UFA may reflect a switch of the
myocardial energy metabolism to the fetal transcriptional program with a reduced rate
of ?-oxidation, which is partially compensated by an increased of glucose utilization
28]. Moreover, Lahey et al. have shown that UFA are more potent activators of TG turnover
than saturated FA in animal models. In decompensated HF, UFA may serve as a beneficial
energy substrate versus FA by upregulating TG dynamics and nuclear receptor signaling
29]. Notwithstanding the scarce evidence, it has been alternatively suggested that myocardial
TG accumulation may be protective against fatty acid-induced lipotoxicity by limiting
the deposition of ceramides and diacylglycerols 30], 31]. Although our study did not provide the mechanisms how TG content mediates cardiac
dysfunction, the in vivo identification of the associations of TG components, particularly
UFA, with cardiac function using 3-T CMR in the post-treated failed heart is an important
step forward.

The mean BMI of the entire study population (comprising both patients and controls)
was 26.1 kg/m
²
, suggesting the presence of overweight according to the World Health Organization
criteria 32]. Previous studies have linked the presence of cardiac steatosis with obesity and
related metabolic diseases 10], 16], 17]. Notably, ectopic TG accumulation within and around the myocardium in moderately
obese individuals has been associated with free fatty acid exposure, generalized ectopic
fat excess, and peripheral vascular resistance 33]. However, we failed to identify significant associations between myocardial TG content
and serum lipid levels. These results suggest that
¹
H-MRS measurements of myocardial TG content may provide complementary clinical information
beyond serum lipid profile.

Limitations

Several caveats of our study merit comment. First, our subgroup analysis is limited
by the small sample size. Although myocardial UFA/TG was positively related with LV
mass and LVEDV, these relationships were fairly weak (r?=?0.39 and 0.24, respectively) and large confidence intervals for the spectral quantification
were evident. Therefore, caution should be exercised in the interpretation of our
findings. Future larger studies will be needed to establish whether myocardial UFA
content may vary between HF patients with different etiologies. Second,
¹
H-MRS measurements of myocardial TG content were not validated by histological examination
of biopsies, mainly because of ethical concerns. Finally, it is unclear whether the
accumulation of myocardial TG results from increased uptake of fatty acids, higher
de novo lipogenesis, or reduced lipid degradation. Further studies are required to clarify
the pathophysiological mechanisms of myocardial TG accumulation in HF patients.